1-naphthenyl- and 1-indenyl-4-substituted phenyl-4-carboxyalkyl piperidines



United States Patent 3,479,363 l-NAPHTHENYL- AND 1-INDENYL-4-SUB- STITUTED PHENYL-4-CARBOXYALKYL PIPERIDINES Alex Meisels, Rolf Denss, and Hugo Ryf, Basel, Switzerland, assignors, by mesne assignments, to Geigy Chemical Eorporation, Ardsley, N.Y., a corporation of New Yor No Drawing. Original application Aug. 26, 1963, Ser. No. 304,656. Divided and this application May 19, 1967, Ser. No. 663,905 Claims priority, application Switzerland, Mar. 30, 1962,

Int. Cl. C07d 29/24, 29/34; A61k 27/00 U.S. Cl. 260294.3 7 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of l-tetrahydronaphthyland l-indanyl-4-aryl-4-carboxyalkyl piperidine derivatives which are useful as analgetics or antitussives. Illustrative compounds are 1-[1-methyl-1,2',3,4'-tetrahydronaphthyl-(Z) ]-4-phenyl-4-carbethoxy-piperidine and 1 l'-ethoxyindanyl-(2) ]-4-phenyl-4-carbethoxy-piperidine. Corresponding dihydronaphthyl and indenyl intermediates are also described.

DETAILED DISCLOSURE This application is a divisional of our application Ser. No. 304,656, filed on Aug. 26, 1963, which is a continuation-in-part of our application Ser. No. 267,814, filed on Mar. 25, 1963, both now abandoned.

This invention relates to new piperidine derivatives which possess valuable pharmacological properties.

It is one object of the present invention to provide new piperidine derivatives which possess improved analgetic activity combined with a low depressive action on the central nervous system.

It is another object of the present invention to provide new piperidine derivatives which are characterized by antitussive activity, accompanied by low analgetic and consequently no habit-forming properties and are, therefore, useful as the active ingredient in antitussive medicaments.

It is known that there are 4-aryl-4-carboXyalkyl-substituted piperidine derivatives which possess an analgetic activity which depends largely on the nature of substituents present at the nitrogen atom of the piperidine nucleus. Especially those derivatives which are substituted at the aforesaid nitrogen atom with a methyl group or with an aliphatic chain which bears in turn, at a distance of at least two carbon atoms from the aforesaid nitrogen atom, an aromatic mononuclear carbocylic radical, are distinguished by very good analgetic properties which have rendered them useful in therapeutic preparations. On the other hand, piperidine derivatives which are substituted at at the aforesaid nitrogen atom with an aliphatic chain bearing a monocyclic aromatic radical at a distance of only one, or other than four carbon atoms from the said nitrogen atom, are useful as analgetics.

It has now been found that, contrary to expectation, substitution of the nitrogen atom of the piperidine nucleus in the above-mentioned class of 4-aryl-4-carboxyalkylsubstituted piperidines with bicyclic hydroaromatic radicals which are directly linked, via their hydrogenated ring portion, to the nitrogen atom of the piperidine nucleus leads to compounds which show, on the one hand, excellent analgetic, and on the other hand, antitussive effects.

are attained especially in the novel compounds described hereinafter.

According to a first aspect of this invention, the novel compounds of the formulas :4 R2 Its-m -N H 000R: 1 ni na 11) wherein, as well as in all following formulas, like symbols have like meanings, namely:

are particularly useful as analgetics on account of their strong analgetic properties, while, for this very reason, they are not recommended for use in antitussive medicaments even in those cases where they possess good antitussive activity, except when simultaneously antitussive and analgetic action is required.

Among the above group of compounds according to the invention, particularly good analgetic activity is shown by those of the formulas wherein R R R R and R have the afore-mentioned meanings, each of R and R represents, independently,

hydrogen, hydroxy, lower alkyl, lower alkoxy or lower alkanyloxy, R represents either hydrogen, or together with R the x0 radical, R represents either hydrogen, or together with R the oxo radical, and at least one of the pairs R R and R R represents hydrogen atoms (Formula (III)A).

According to another aspect of the invention, the novel compounds of the formula and more particularly those of the formulas wherein R' is hydrogen, hydroxy, lower alkyl, or lower alkanoyloxy and R and R have the meanings given above, have strong antitussive activity while the analgetic component in their pharmacodynamic spectrum is sufiiciently weaker than that of the compound of Formulas I and II, so that they are very well suited for use as active ingredients in antitussive medicines.

The novel compounds of the formulas (VIDA and wherein R R R and K, have the above given meanings and R represents hydrogen or lower alkyl, as well as the compounds of Formula I supra which contain a halogen, preferably a chlorine or bromine atom in lieu of R are suitable as intermediates in the production of the active componeints described hereinbefore, by methods to be described further below.

The pharmacodynamic spectra of the compounds of Formulas I to VII (A and B) comprise analgetic, antitussive, spasmolytic, anestheticse-potentiating and only weak sedative components which render these compounds useful as the active ingredients in pharmaceutical preparations for the abovementioned purposes.

Analgetic preparations containing the above analgetically active substances as active ingredients, are distinguished by low centrally depressory side effects. Those bearing a hydroxyl or lower alkyl group at the hydrogenated ring portion of the bicyclic nucleus in a-position to the nitrogen atom of the piperidine nucleus, are particularly spasmolytically active.

In all definitions where lower is used herein as well as in the appended claims, in connection with alkyl and the like aliphatic radicals, radicals with a total of from one to four carbon atoms are meant.

The compounds according to the invention, represented by Formulas I to VII (A and B) inclusive can be administered as such or in the form of their pharmaceutically acceptable, non-toxic salts, perorally or rectally and, in the form of aqueous solutions of their salts, also parenterally.

Acids suitable for salt formation are, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, fi-hydroxyethane sulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, itric acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.

Pharmaceutically acceptable salts, i.e. salts with pharmaceutically acceptable acids which, in the necessary dosages are pharmacologically harmless, can be used as active substances for oral or parenteral administration. Salts with other acids are suitable, for example, for recrystallization in order to purify the new compounds.

The above-described compounds of Formulas I to IX acording to the invention are produced by a process which leads to the production of compounds of the general formula which comprises the aforesaid compounds of Formulas I to IX inclusive, and wherein R R 'R and R have the above-given meanings, and X represents a straight-chain, saturated or mono-unsaturated trivalent alphatic hydrocarbon radical having 3 to 5 carbon atoms, two free terminal linkages of which, at different carbon atoms, are bound to the benzene nucleus A and which can be substituted by an oxo radical, a hydroxyl group, a lower alkoxy or a lower alkanoyloxy radical, and/or by maximally two lower alkyl radicals, or, in the case of intermediates, by a chlorine atom, and which process comprises (a) reacting a compound of the general formula wherein R and R have the above-given meanings, if necessary, in the presence of an acid binding agent, and preferably in an organic inert solvent medium, such as anhydrous ethanol, butanol, isopropanol, benzene or toluene, at elevated temperature, preferably at the boiling temperature of the solvent mixture, with a reactive ester of an alcohol of the general formula R4 (XII) wherein R R and X have the above-given meanings and an acid, described more in detail below, and then recovering the resulting products of Formula X by conventional methods.

If necessary, acid-binding agents such as sodium or potassium carbonate or tertiary organic bases, in particular lower trialkyl-amines, di-lower alkyl-phenylamines, or pyridines such as, for example, triethylamine, tri-n-butyl-amine, N,N-dimethyl-aniline or pyridine are added to the reaction mixture.

In the starting compound of Formula XI, R can be, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl radical, and R can be, for example, phenyl, methylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, ethoxyphenyl, npropoxyphenyl, isopropoxyphenyl, n-butoxyphenyl, isobutoxyphenyl or chlorophenyl.

Reactive esters of alcohols of the general formula XII are, in particular, hydrohalic acid esters, i.e. bromides and chlorides as well as lower alkane and lower alkylphenyl sulfonic acid esters such as p-toluene sulfonic acid ester and methane sulfonic acid ester. The reactive esters can also be derived from enols, i.e. the halogen atom or sulfonyloxy group taking part in the reactions may be at a carbon atom which is linked by a double bond to a neighbouring C-atom of ring-part X. In addition to any bromine or chlorine atom present as reactive ester component, there can also be a chlorine atom present in X which, because of its position in the molecule, is less reactive and remains as a substituent of the radical X in the final product of Formula X.

Independently of each other R and R are, in Formula XII above, e.g. hydrogen, methyl, ethyl, n-propyl, isopropyl, tert. butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy radicals. In addition R can be, e.g. the acetoxy, propionoxy, or butyroxy radical, a hydroxyl group, a chlorine, bromine or fluorine atom or the amino, formyl'amino, acetylamino, propionylamino or butyrylamino group. The trivalent radical X is, e.g. a 1- propanyl-3-ylidene or 1,2,3-propantriyl radical, a l- -butanyl-4-ylidene or 1,2,4-butantriyl radical, a l-pentanyl- 5-ylidene, 1,2,5-pentantriyl or 1,3,5-pentantriyl radical, a l-propene-1-yl-3-ylidene, 2-propene-1-yl-3-ylidene, 2 butene-1-yl-4-ylidene, 3 butene-l yl 4 ylidene, l-butene- 1,2,4-triyl, 1-butene-1,3,4-triyl or 2-butene-1,2,4-triyl radical, a 4-pentene-l-yl-5-ylidene or 2-pentene-l,2,5-triyl radical.

These trivalent radicals can be substituted, e.g. by one to two low alkyl radicals having together at most 7 carbon atoms whereby they are transformed into branched chained aliphatic hydrocarbon radicals having in all at most 12 carbon atoms. Examples of lower alkyl radicals are in particular methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl, and tert. butyl radicals. Another substituent of trivalent radical X, in particular at a methylene group which may be alkyl substituted, can be a hydroxyl group, a methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, acetoxy, propionoxy or butyroxy radical or at an unsubstituted methylene group only an X0 radical.

Various starting materials of the general Formula XI and numerous reactive esters of compounds of the general Formula XII are known and others can be produced in an analogous manner. Examples of reactive esters of compounds of the general Formula XII are, for instance: l-chlordindane, l-bromoindane, l-hydroxy-Q-bromoindane, l-methoxy-Z-bromoindane, 1-ethoxy-2-bromoindane, l-propoxy-Z-bromoindane, Z-bromoindanone-(l), 3-bromoindanone-( 1), l-chlorotetralin, 2-chlorotetralin, l-bromoindene, l-bromotetralin, 2-bromotetralin, 1- hydroxy-Z-bromotatralin, 2-bromotetralone-(1), 5-chloro 6,7,8,9-tetrahydro-5H benzocyclo-heptene, 7-bromo-6,7,8, 9-tetrahydro-iH benzo-cycloheptene and 7 (p toluenesulfonyloxy) -6,7,8,9-tetrahydro-SH-benzocycloheptene.

A group of compounds of the general Formula X which is characterized by Formula XIV, infra, is obtained by a second process which comprises reacting a compound of the general Formula XI given above wherein R and R have the meanings there given with a compound of the general formula a temperature in the range of about 50 to C. and, if necessary, in the presence of an inert aromatic hydrocarbon solvent such as benzene, toluene or xylene, whereby a compound of the general formula is obtained. In this formula, which is comprised by Formula X above, R R R R R Y and Z have the above-stated meanings.

Examples of starting materials of the general Formula XIII are, for instance: 1,2-epoxyindane, 2,3-epoxytetralin, 2,3-epoxy-5-methyltetralin, 1,4-diethyl 2,3-epoxytetralin and 5,6-epoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene. In these compounds, Y is the methylene or trimethylene radical and Z is the direct bond or the methylene radical.

A third process for the production of compounds of Formula X, namely those resulting from the starting compound of Formula XV, comprises (a) reacting a compound of the general Formula XI given above wherein R and R have the meanings there given at elevated temperature e.g. in suitable inert organic, preferably aromatic hydrocarbon solvents such as benzene, toluene or xylene or without such solvent the water formed in the reaction being continuously distilled off, and advantageously with the exclusion of oxygen, e.g. in an atmosphere of nitrogen, with the above-mentioned compound of formula wherein Y' and Z represents alkylidene or alkylene radicals which complete the l-ethyl-Z-ylidene radical or a l-lower alkyl-1-ethenyl-2-ylidene radical contained in the general Formula XVI infra to a radical corresponding to the definition of X supra, wherein one of X and Z' can also be the direct carbon-to-carbon bond, and R R and R have the meanings given above, and if desired, (b) reacting the resulting product of the general formula in those cases in which R in the latter is hydrogen, with a reactive ester of methanol, preferably a methyl halide, in particular methyl iodide, in a suitable inert organic solvent, preferably such as dioxan, performing the reacton at elevated temperature, preferably at about 30 to 60 C., and, if necessary, in a closed vessel, there- 'by obtaining the corresponding methyl-substituted immoniurn salt, in particular an immonium halide such as the iodide, and finally, if desired, (0) reducing or hydrogenating the semicylic double bond of the said methylsubstituted immonium salt, or, if so desired, reducing or hydrogenating the reaction product of Formula XV-I, supra, directly. The reduction under step (c) can be carried out in the cold, or, if necessary, with heating, e.g. with the aid of sodium boronhydride potassium boronhydride as hydrogenating agent in an organic medium, such as methanol, ethanol, isopropanol, diethyleneglycol, dimethylether, in which, preferably, both the compound to be reduced as Well as the alkali metal boronhydride are at leastpartially soluble. Also boiling in anhydrous formic acid is a suitable method for reducing enamines of the general Formula XVI.

Numerous starting materials of the general Formula XV are known and others can be produced analogously.

(XVI) The following compounds are given as examples of such starting materials:

indanone-( l 3-methylindanone-( 1 4-bromo-7-methylindanone-( l indanone-(Z),

l-methylindanone- 2) l-ethylidanone-(Z), l-n-propylidanone- 2) tetralonel 2-methyltetralone-( 1), 7-methyltetralone-( 1 7-isopropyltetralone-(1),

2,3 -dimethyltetralone- 1 2,5 -dimethyltetralone-( l 4,7-dimethyltetralone-( 1 5,7-dimethyltetralone-( 1 6,7-dimethyltetralone-( 1 2,4,7-trimethyltetralone-( 1 5-methoxytetralone-( 1 7 -chlorotetralone- 1), 6-acetylaminotetralone- 1 6-ethoxycarbonylaminotetralone-( 1 tetralone- (2) l-methyltetralone- 2) l-ethyltetralone- (2) l-n-propyltetralone- 2 6-methoxytetralone- (2 6,7,8,9 -tetrahydro-SH-benzocycloheptenone- 5 3-methoxy-6,7,8,9-tetrahydro-SH-benzocycloheptenone- 6,7,8,9-tetrahydro-SH-benzocycldheptenone- (7 and 6-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptenone- Representatives of the symbols Y and Z in general Formulas XV and XVI are the same radicals as given for Y and Z, for Example Y is the direct linkage, a methylene, ethylene or propylene radical and Z is the direct linkage, a methylene, ethylidene, ethylene, propylene o1 trimethylene radical.

Subsequent conversions can be made at the end of each of the above-described three production processes, and are of importance, for example because the second process which is valuable due to the starting materials being readily accessible and very reactive only leads, directly, to reaction products having a hydroxyl group as substituent of X, and because there are great differences with regard to accessibility of the starting materials for the first process, which differences permit the subsequent introduction of a substituent, in some cases, to be performed more advantageously by modification of an intermediary substituent, rather than by introduction of such substituent directly into the starting material. Depending on the process employed and on the starting material, both the etherification or acylation of hydroxyl groups as well as the liberation thereof from acyloxy groups, as well as the reduction of oxo radicals to hydroxyl groups and, invertedly, the oxidation of hydroxyl groups to oxo radicals, the acylation of amino groups as well as the liberation thereof from acylamino groups, can be of advantage. In the same way, the splitting off of hydrogen halide or water both for the purpose of production of an unsaturated compound of general Formula X as well as a mere intermediate step in the elimination of an original hydroxyl group, followed by a hydrogenation, can be performed. The modifications of primary reaction products illustrated below can also be made to the products of the third process mentioned.

If desired, a primary reaction product having a hydroxyl group or groups as R and/ or in X is etherified to a compound of general Formula X having one or two alkoxy groups in the corresponding positions. The etherification is performed, e.g. by reacting corresponding primary reaction products with reactive esters of a lower alkanols, in particular with lower alkyl halides, dialkyl sulfates or aryl sulfonic acid alkyl esters, in the presence of acid binding agents. Alkali metals and derivatives thereof such as sodium amide or sodium hydride for example can serve as such agents, by means of which the primary reaction products containing hydroxyl groups can be converted into their alkali metal compounds, advantageously immediately before the second reaction.

In addition, the etherification can also be performed, for example, by means of diazomethane and boronfluoride/ether complex or ether/methylene chloride, or by means of lower alkanols in the presence of agents which split off water such as, eg sulfuric acid or p-toluene sulfonic acid.

Also, a primary reaction product having a hydroxyl group or groups as R, and/or in X can be acylated to a compound of the general Formula X having one or two lower alkanoyloxy groups in the corresponding positions. The acylation is performed, e.g. by reacting in pyridine, halides or anhydrides of lower alkanoic acids, e.g. acetic acid, propionic acid, butyric acid or isobutyric acid, with the primary reaction products, or with sodium compounds of the primary reaction products in inert organic solvents. It can also be performed, eg by reacting lower alkanoic acids with the primary reaction products in the presence of agents splitting off water.

In reverse, if desired, a primary reaction product having an alkanoyloxy group or groups as R and/ or as substituent in X is hydrolyzed into a compound of general Formula X having one or two hydroxyl groups in the corresponding positions. The hydrolysis can be performed, e.g. by means of alkanolic alkali metal hydroxide solutions under mild reaction conditions without the radical R being split off. The alkali metal hydroxide solution is used in the stoichiometric ratio corresponding to the number of low alkanoyl radicals to be split off. Also acid hydrolysis can be used, egg. by means of aqueous or aqueous/alkanolic hydrochloric acid, or, when suitable reaction conditions are chosen, an alkanoyloxy group can be split during the primary reaction. The use of starting materials which lead to primary reaction products having one or two alkanoyloxy groups instead of the desired hydroxyl groups in the end products, can be of interest for various reasons. For example, in a suitable hydroxy-oxo compound, first the hydroxyl group can be acylated, then the oxo radical reduced and the alkanoyloxy-hydroxy compound of the general Formula XII obtained can be converted into a reactive ester; or it can be of advantage in the production of epoxides of general Formula XIII by oxidation of corresponding unsaturated compounds, to protect a hydroxy group R by alkanoylation.

Another possibility for the introduction of a free hydroxyl group into the radical X of a primary reaction product of general Formula X consists in reducing or hydrogenating such a product containing an oxo radical in X to form a compound of the general Formula X having a hydroxyl group in the corresponding position. The reduction can be performed in the cold or, if necessary, in the warm, by means of, e.g. sodium or potassium boronhydride in a suitable organic or organic/aqueous medium such as eg diethylene glycol dimethyl ether. The hydrogenation can be performed, e.g. in the presence of Raney nickel or noble metal catalysts such as palladium or charcoal or barium carbonate, in an organic solvent such as dioxan or ethanol. The value of this process lies in the fact, for example, that various a-halogen ketones are available as easily accessible reactive esters of compounds of the general Formula XII, in which compounds the oxo radical could not have been or only could have been reduced or hydrogenated with much more difiiculty before the reaction with a compound of general Formula XI.

On the other hand, particularly in the second process mentioned, primary reaction products having a hydroxyl group in X are obtained in a simple manner. These reaction products are converted, if desired, into compounds of the general Formula X having an oxo radical in the corresponding position by treating them with an oxidizing agent, for example with chromium trioxide in glacial acetic acid at room temperature or in pyridine in the warm.

Whilst the above is concerned with conversions of the hydroxyl group with preservation of the oxygen atom of the latter group, there are also further conversions involving the elimination of said oxygen atom. The reason therefore is again the simple production of certain primary reaction products having a hydroxyl group as substituent of X, here in comparison to, for example, desired end products having a halogen-substituted or unsaturated radical X.

Thus, if desired, a compound of general Formula X having a hydroxyl group in X, which itself can be a primary reaction product or which can be obtained by one of the conversions previously mentioned, or an alkali metal compound thereof, is converted into a compound of general Formula X having a chlorine atom in the corresponding position by treatment with a sulfonic acid chloride, in particular methane sulfonic acid chloride, or with an inorganic acid chloride such as thionyl chloride, or also with phosgene or oxalylchloride, in a suitable inert organic solvent such as, e.g. benzene.

In addition, if desired, the compound of general Formula X obtained as above having a chlorine atom in X is converted into a compound of Formula X having a double bond in X by treatment at elevated temperature with an inorganic or organic base, e.g. with a sodium alkanolate in the corresponding alkanol, or with collidine, or a compound of general Formula X having a hydroxyl group in X is converted into the compound of Formula X having a double bond in X by splitting oil water. The water is split 01f, e.g. by treatment with suitable agents such as phosphorus pentoxide or potassium bisulfate at raised temperature or, particularly when the hydroxyl group is bound to a tertiary carbon atom, by simple heating, e.g. distillation under reduced pressure.

The compounds of general Formula X having a double bond in X obtained as described above or, in certain cases, as primary reaction products, are hydrogenated, if desired, to the corresponding compounds without a double bond in X, e.g. in the presence of Raney nickel or a noble metal catalyst, in a suitable organic solvent such as dioxide or ethanol. Starting from a primary reaction product having a hydroxyl group or an x0 radical in X, the above reactions together form a suitable series for the elimination of a hydroxyl group or an 0x0 radical and make it possible, for example, to attain compounds having an unsubstituted radical X by the second production process.

Compounds of general Formula X having a free amino group R are produced by hydrolyzing a primary reaction product of general Formula X with a lower alkanoylamino group R for example by means of moderately concentrated hydrochloricacid or by means of alkanolic or aqueous/alkanolic alkali lye. Also, with a suitable choice of reaction conditions, a low alkanolyamino group R can be split 01? during the primary reaction.

Invertedly, a primary reaction product of the general Formula X having an amino group R can be acylated to a corresponding compound having a low alkanoylamino group R for example by treatment with a low alkanoic acid halide or anhydride, if nececssary in the presence of an acid binding agent such as, e.g. pyridine, or by treatment with an alkali carbonate in an organic solvent or with sodium hydroxide solution in a two-phase organic/aqueous system. The acetyl radical is most simply introduced, e.g. by boiling a primary reaction product having a free amino group in excess acetic anhydride.

The compounds of general Formula X are converted in the conventional manner into their salts with inorganic or organic acids.

10 EXAMPLE 1 (a) 14.5 g. of 4-phenyl-4-carboethoxy-piperidine carbonate (4-pentyl-isonipecotinic acid ethyl ester carbonate, produced according to Thorp and Walton, J. Chem. Soc., 1948, 559) in 25 ml. of anhydrous butanol are refluxed for 1 hour. A solution of 11.4 g. of 1-hydroxy-2-bromotetralin (produced according to Straus and Rohrbacher, Bor., 54, 40 (1921)) in 50 ml. of anhydrous butanol is then slowly added dropwise and the mixture is refluxed for another 14 hours. The butanol is distilled ofif in vacuo and the oily residue is dissolved in ether and 1 N hydrochloric acid and extracted several times with ml. of N hydrochloric acid. The combined acid solutions are then made alkaline with 1 N sodium hydroxide solution and extracted twice with ether. To separate from nonreacted 4-phenyl-4-carboethoxy-piperidine, solid carbon dioxide is added to the other extract whereupon the starting material mentioned precipitates in the form of the carbonate and can be filtered off. The 1-2'-[hydroxy- 1,2',3',4' tetrahydronaphthyl (1')]-4-phenyl-4-carboethoxy-piperidine formed by rearrangement and obtained by distilling off the solvent from the ethereal filtrate, is not crystalline and is purified, therefore, by way of the hydrochloride. To obtain the hydrochloride, 10 g. of the crude base are dissolved in 50 ml. of abs. ether and the calculated amount of cold saturated ethereal hydrochloric acid is added while cooling with ice. The hydrochloride obtained melts after recrystallisation from methanol/ether at 192-193". Hydrobromide, M.P. 112115 Maleate, M.P. 137-138.

(b) To produce 1-[2-pyacetoxy-1',2',3',4'-tetrahydronaphthyl (1')]-4-phenyl-4-carboethoxy piperidine, 3.2 g. of the above hydroxy base in 10 ml. of abs. pyridine and 10 ml. of acetanhydride are left to stand for 14 hours at room temperature. After distilling off the reactants in vacuo, the crude product which remains is dissolved in 500 ml. of ether and washed several times with 10% sodium carbonate solution and water. It is recrystallised from ether/pentane and then melts at 107-108". Hydrochloride, M.P. 193-194.

(c) To produce l-[2'-propionoxy-1',2',3',4'-tetrahydronaphthyl-( 2) ]-4-phenyl-4-carboethoxy-piperidino, 2.9 g. of the above hydroxy base are dissolved in 10 ml. of abs. pyridino, 1.5 ml. of propionyl chloride are added while cooling and the reaction mixture is left to stand for 14 hours at room temperature. It is then dissolved in 500 ml. of ether and washed several times with 5% sodium bicarbonate solution and water. The ether is distilled off, the residue is dissolved in a mixture of benzene and hexane (5:2) and filtered according to Brockmann through 25 times the amount of aluminium oxide, activity II. After distilling ofi the solvent, the product which remains is recrystallised from ether/pentane and then melts at 104105. Maleate, M.P. 76-86".

EXAMPLE 2 1-[1' methoxy-1',2',3,4-tetrahydronaphthyl-(2')]-4- phenyl-4-carboethoxy-piperidine is produced analogously to Example 1(a) starting from 14.5 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 12.5 g. of l-methoxy- 2-bromotetralin (which latter is produced according to Straus and Rohrbacher Bon, 54, 40 (1921)). It melts at 63-65". Hydrobromide, M.P. 191-192.

EXAMPLE 3 1-[1'-ethoxy-1',2,3,4' tetrahydronaphthyl (2)]-4- phenyl-4-carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 1 4.5 g. of 4-phenyl-4-carboethoxy-piperidino carbonate and 12.8 g. of 1-ethoxy-2- bromotetralin (which latter is produced analogously to the methoxy compound, see Example 2). M.P. 82-83. Hydrochloride, M.P. 199-200".

1 1 EXAMPLE 4 1 [1 n propoxy 1',2',3',4 tetrahydronaphthyl- (2')] 4 phenyl 4 carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 14.5 g. of 4- phenyl-4-carboethoxy-piperidine carbonate and 13.5 g. of 1 n-propoxy-2-bromotetralin (which latter is produced analogously to the methoxy compound, see Example 2). It melts at 59-60". Hydrochloride, M.P. 181-183.

EXAMPLE 5 (a) 1- [2 hydroxy indanyl (1')] 4 phenyl 4- phenyl-4-carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 14.5 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 10.7 g. of l-hydroxy- 2-bromoindane (which latter is produced according to Treibs and Schroth, Ann., 639, 204 (1961)). It melts at 114-115". Hydrochloride, M.P. 186-187".

(b) 1 [2' acetoxy indanyl (1')] 4 phenyl 4- carboethoxy-piperidine is obtained analogously to Example 1(b) starting from 5 g. of the above hydroxy base and a mixture of ml. of abs. pyridine and 10 ml. of acetanhydride. M.P. 100-102. Hydrochloride, M.P. 139- 141.

(c) 1-[2' propionoxy indanyl (1')] 4 phenyl- 4-carboethoxy-piperidine is obtained analogously to Example 1(c) starting from 9.1 g. of the above hydroxy base and 2.5 ml. of propionyl chloride. M.P. 67-68". Hydrochloride, M.P. 122-125".

EXAMPLE 6 1 [1 methoxy indanyl (2')] 4 phenyl 4- carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 18.5 g. of 4-phenyl-4-carboethoxypiperidine carbonate and 16 g. of 1-methoxy-2-bromoindane (which latter is produced analogously to l-methoxy-2-bromotetralin, see Example 2). It melts at 73-74". Hydrobromide, M.P. 206-207.

EXAMPLE 7 1 [1' ethoxy indanyl (2')] 4 phenyl 4- carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 18.5 g. of 4-phenyl-4-carboethoxypiperidine carbonate and 16.8 g. of 1-ethoxy-2-bromoindano (which latter is produced analogously to l-methoxy-2-bromotetralin, see Example 2). It melts at 9899. Hydrochloride, M.P. 215-216".

EXAMPLE 8 1 [1' n propoxy -indanyl (2')] 4 phenyl 4- carboethoxy-piperidine is obtained analogously to Example 1(a) starting from 35.3 g. of 4-phenyl-4-carboethoxypiperidine carbonate and 17.1 g. of 1 n proproxy 2- bromoindano (which latter is produced analogously to the methoxy compound, see Example 2). It boils at 188- 189 under 0.006 mm. Hydrobromide, M.P. 225-226".

EXAMPLE 9 1 [1',2,3,4 tetrahydronaphthyl (2')] 4 pheny1-4-carboethoxy-piperidine is produced analogously to Example 1(a). g. of 4-phenyl-4-carboethoxy-piperidine carbonate are used as starting material but before the addition of 12.5 g. of 2-chlorotetralin (produced according to Richtzenhain, Chem. Ber., 81, 96 (1948)), all the solvent is distilled off in vacuo and then the mixture is heated at 100 for 24 hours. M.P. of the base 97-98; of the hydrochloride 199200; of the methane sulphonate 194-196. Compare Examples 17 and 30.

EXAMPLE 10 1 [1' oxo 1,2,,3',4' tetrahydronaphthyl (2')]- 4-phenyl-4-carboethoxy-piperidine is obtained analogously to Example 1(a), 22.5 g. of 4-phenyl-4-carboethoxypiperidine carbonate and 9.5 g. of 2-bromotetralone-(1) (produced according to Straus et al., Ann., 444, 178 (1925)) being used as starting material and 200 ml. of

12 benzene being used as solvent. Hydrochloride, M.P. 206- 211.

' EXAMPLE 11 1 (1 indanyl) 4 phenyl 4 carboethoxy-piperidine is produced analogously to Example 1(a) starting from 21.1 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 6.1 g. of l-chloroindane (produced according to Weissgerber, Ber., 44, 1442 (1912)), on using 200 ml. benzene as solvent. M.P. 94-95. Hydrochloride, M.P. 167-169.

EXAMPLE 12 (a) 1 (6',7,8',9' tetrahydro 5H benzocycloheptene-7'-yl)-4-phenyl-4-carboethoxy piperidine is obtained analogously to Example 1(a) starting from 15.8 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 13.4 g. of 7 bromo 6,7,8,9-tetrahydro-5H-benzocycl0 heptene (for production thereof see below) with the addition of 24 g. of anhydrous sodium carbonate and using 200 ml. of ethylene glycol monoethyl ether as solvent. M.P. 87-88". Methane sulphonate, M.P. 205-206".

In addition to the 1-(6',7,8',9'-tetrahydro-5'H-benzocycloheptene-7'-yl)-4-phenyl 4 carboethoxy-piperidine, also a slight amount of 1 (6',7',8,9' tetrahydro-SH- benzocycloheptene (6 yl) 4-phenyl-4-carboethoxypiperidine, M.P. 84-87", is obtained. Sulphate, M.P. 243- 244.

To separate the two isomers, the mixture which precipitates is dissolved in hexane and filtered according to Brockmann through 25 times the amount of aluminium oxide activity II. The isomer having the piperidine ring in the 6'-position is eluted in the first hexane fractions whilst that having the piperidine ring in the-7-position is contained in the later fractions.

Preparation of 7 bromo-6,7,8,9-tetrahydro-5H-benzocycloheptene: 16 g. of 6,7,8,9-tetrahydro-5H-benzocycloheptene-7-one (produced according to Allinger et al., J. Org. Chem., 27, 722 (1962), regarding nomenclature see Ring Index, 1960, p. 239), are reduced to 6,7,8,9-tetrahydro-SH-benzocycloheptene-7-ol (M.P. 96-97") by boiling with 2 g. of lithium aluminium hydride in 300 ml. of abs. ether for 4 hours. 13 g. of this alcohol are converted into 7 bromo 6,7,8,9-tetrahydro-SH-benzocycloheptene (B.P. =153-156) by treatment with 8.8 g. of phosphorus tribromide, first at 5 and then for 2 hours at 20 and 1 hour at 100.

(b) 1 (6,7',8,9' tetrahydro-5'H-benzocycloheptene- 7' yl) 4 phenyl 4 carboethoxy-piperidine is also obtained if 5.28 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 3.90 g. of 7-(p-toluene sulphonyloxy)-6,7,8,9- tetrahydro 5H benzocycloheptene (M.P. 124-125 are heated for 14 hours at 100. M.P. 87-88. Methane sulphonate, M.P. 205-206.

The 7- (p toluene sulphonyloxy-6,7,8,9-tetrayhdro- SH-benzocycloheptene is produced from 6,7,8,9-tetrahydro 5H benzocycloheptene-7-ol by treatment with ptoluene sulphonyl chloride in the presence of pyridine.

EXAMPLE 13 (a) 7.9 g. of 4 phenyl 4 carboethoxy-piperidine carbonate are dissolved in 100 ml. of abs. benzene and the solution is refluxed until no more carbon dioxide is developed. The solvent is distilled off in vacuo and the 4-phenyl-4-carboethoxy-piperidine which remains and 4.4 g. of 2,3-epoxytetralin, (produced according to Cook and Hill, I.A.C.S., 62, 1995 (1940)), are heated for 5 hours at 100. After cooling, 500 ml. of ether are added to the reaction mixture, and the whole is extracted several times with 100 ml. of 1 N hydrochloric acid. 1 N sodium hydroxide solution is added to the combined acid solutions and the precipitated salt until the reaction is alkaline and the mixture is extracted twice with ether. Non-reacted 4 phenyl 4 corboethoxy piperidine is separated by the addition of solid carbon dioxide'to the ether solution. After distilling off the solvent, 1-[3-hydroxy-1,2',3',4'

13 tetrahydronaphthyl (2')]4-phenyl 4 carboethoxy-piperidine remains in the form of White crystals which, after recrystallisation from acetone/hexane, melt at 117- 118. Hydrochloride, M.P. 224-225 (b) l [3 acetoxy 1',2',3',4-tetrahydronaphthyl- (2')] 4 phenyl 4 carboethoxy-piperidine is obtained analogously to Example 1(b) starting from g. of the above hydroxy base and a mixture of ml. of abs. pyridine and 10 ml. of acetanhydride, M.P. 82-83". Hydrochloride, M.P. 185-186.

(c) 1 [3' propionoxy 1',2',3,4'-tetrahydronaphthyl-(2)] 4 phenyl 4 carboethoxy-piperidene is obtained analogously to Example 1(c) starting from 2.9 g. of the above hydroxy base and 1.5 m1. of propionyl chloride, M.P. 98-99". Hydrochloride, M.P. 190-195 EXAMPLE 14 (a) 1 [3' hydroxy 8'-methy1-1',2',3',4'-tetrahydronaphthyl (2')]-4-phenyl-4-carboethoxy-piperidine is obtained analogously to Example 13(a) starting from 8.2 g. of 4-phenyl-4-carboethoxy-piperidine and 5 g. of S-methyl- 2,3-epoxytetralin (for production see below); M.P. 150. Hydrochloride, M.P. 243-245.

5-methyl-2,3-epoxytetralin is obtained from 1,4 dihydro-S-methyl-naphthalene (produced according to Huckel and Vevera, Ber., 95, 350 (1962)), with perbenzolic acid in chloroform solution, M.P. 90.

(b) 1 [3 acetoxy-8-methyl-1,2,3',4'-tetrahydro naphthyl (2')] 4 phenyl-4-carboethoxy-piperidine is obtained analogously to Example 1(b) starting from 2 g. of the above hydroxy base and a mixture of 1-0 ml. of abs. pyridine and 10 ml. of acetanhydride, M.P. 120. Hydrochloride, M.P. 200-204.

EXAMPLE 1 [1,4' diethyl 3' hydroxy-1',2',3',4-tetrahydronaphthyl (2')] 4 phenyl-4-carboethoxy-piperidine is obtained analogously to Example 13 (a) starting from 13.2 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 10.1 g. of 1,4-diethyl-2,3-epoxytetralin (for production thereof see below); B.P. 168-175".

Preparation of 1,4 diethyl 2,3-epoxytetralin: 1,4-diethyl 1,4 dihydronaphthalene is obtained according to Huckel and Jennewein, Chem. Ber., 95, 350 (1962) from naphthalene with sodium and ethyl iodide in liquid ammonia; B.P. 7075. 1,4 diethyl-2,3-epoxytetralin is formed therefrom by the action of benzoic peracid in chloroform according to Cook and Hill, I. Am. Chem. Soc., 6 2, 1995 (1940 B.P. 147-154".

EXAMPLE 16 43.5 g. of 4-phenyl-4-carboethoxy-piperidine carbonate are dissolved in 200 ml. of benzene and the solution is heated in a vessel fitted with a water separator until no more carbon dioxide is developed and until the slight amount of water still in the solution has been removed. 24 g. of tetralone-(Z) are then added and the reaction mixture is heated for 12 hours in the water separator under an atmosphere of nitrogen. The solution is then concentrated in vacuo and the residue, l-[3',4'-dihydronaphthyl (2')] 4 phenyl-4-carboethoxy-piperidine, is recrystallised from ethanol. M.P. 103-104 with decomposition.

1- [indenyl- (2') ]-4-phenyl-4-carboethoxy-piperidine can be produced in an analogous manner from indanone-(Z) and 4-penyl-4-carboethoxy-piperidine carbonate. After recrystallising twice from benene/ petroleum ether it melts at 140-142.

EXAMPLE 17 10.85 g. of l [3,4 dihydronaphthyl-(Z')]-4-phenyl- 4-carboethoxy-piperidine (see Example 16) are dissolved by warming in 100 ml. of diethylene glycol dimethyl ether and the solution is added dropwise to 4.5 g. of sodium borhydride dissolved in 100 ml. of diethylene glycol dimethyl ether. The reaction mixture is then stirred for 2 hours at 45 and subsequently at room temperature. The somewhat turbid solution is then diluted with 700 ml. of ether and repeatedly extracted with dilute hydrochloric acid. The combined hydrochloric acid extracts are made alkaline at 0 with concentrated sodium hydroxide solution and exhaustively extracted with ether. After drying the ether with sodium sulphate and evaporating, 1- [1',2,3',4-tetrahydronaphthyl-(2)] 4 phenyl 4-carboethoxy-piperidine is obtained which, after recrystallising twice from methanol, melts at 97-98. Hydrochloride melting point 199200. Methanol sulphonate, M.P. 194-196". See Examples 9 and 30.

1 [indanyl (2')] 4-phenyl-4-carboethoxy-piperidine can be produced in an analogous manner from l-[indenyl- (2)]-4-phenyl-4-carboethoxy-piperidine. M.P. 127128. Hydrochloride, M.P. 235237.

EXAMPLE 18 6.1 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 3.7 g. of l-methyl-tetralone-(Z) (B.P. 93, see I. Am. Chem. Soc., 76, 2029 (1954)) are dissolved in ml. of toluene and the solution is boiled in a flask fitted With a water separator for 14 hours under an atmosphere of nitrogen. The solution is then evaporated in vacuo, the residue is dissolved in 100 ml. of ether and nonreacted 4-phenyl-4-carboethoxy-piperidine is precipitated from this solution in the form of the carbonate and is filtered 01f. 0.48 ml. of anhydrous formic acid are added to the 1-[l'-methyl-3',4-dihydronaphthyl- (2') ]-4-phenyl- 4-carboethoxy-piperidine (4.7 g.) obtained from the ethereal filtrate by distilling off the solvent and the whole is heated for 2 hours at 100 ml. of dilute sulphuric acid are then added to the reaction mixture and the whole is extracted with ether. The acid solution is made alkaline at 0 with concentrated sodium hydroxide solution and exhaustively extracted with ether. After drying the ether and evaporating, 1-[l-methyl-l',2',3',4-tetrahydronaphthyl-(Z)]-4-phenyl-4-carboethoxy-piperidine is obtained. After recrystallisation from methanol it melts at 97-99". Sulphate, M.P. 190195.

The following compounds can be produced in an analogous manner from 4-phenyl-4-carboethoxy-piperidine carbonate: 1 [1' ethyl 1,2',3',4 tetrahydronaphthyl- (2')] 4 phenyl 4 carboethoxy piperidine (using l-ethyl-tetralone-(Z), B.P. 140145), M.P. 81-82": hydrochloride, M.P. 182l84; 1[1-n-propyl-l',2,3',4'- tetrahydronaphthyl (2')] 4 phenyl 4 carboethoxypiperidine (using 1-n-propyl-tetralone-(2), B.P. 143- 151), M.P. 111112, hydrobromide, M.P. 205-206; 1 [1' ethyl indanyl (2')] 4 phenyl 4 canboethoxy-piperidine (using l-ethyl-indanone-(Z), B.P. l25 130), M.P. 79-80; sulphate, M.P. 176178; 1-[1'-npropyl indanyl (2')] 4 phenyl 4 carboethoxypiperidine (using l-n-propyl-indanone-(Z), B.P. 146- M.P. 104105; methane sulphonate, M.P. 151- 152; 1 [6' methoxy 1',2',3',4' tetrahydronaphthyl- (2')] 4 phenyl 4 carboethoxy piperidine (using 6-methoxy-tetralone-(2) prepared according to Nelson, J. Am. Chem. Soc., 82, 2575 (1960)), B.P. 130-140; and 1 [6 methyl 1,2,3',4 tetrahydronaphthyl- (2')] 4 phenyl 4 carboethoxy piperidine (using 6-methyl-tetralone-(2)), B.P. l20130; hydrochloride, M.P. 210; sulphate, M.P. 223.

EXAMPLE 19 2.64 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 2.92 g. of tetralone-(l) are dissolved in 5 ml. of toluene and the solution is heated in a fiask fitted with a water separator under an atmosphere of nitrogen in an oil bath of 180400". After evaporating and recrystallising from ethanol/ ether, the 1-[3',4'-dihydronaphthyl-(1)]-4- phenyl-4-carboethoxy-piperidine so obtained melts at 85 .5- 87.5

The 1 [l',2',3',4' tetrahydronaphthyl (1')] 4- phenyl-4-carboethoxy-piperidine is obtained analogously 15 to Example 18 from 1-[3,4'-dihydronaphthyl-(1)]-4- phenyl-4-carboethoxy-piperidine by treatment with anhydrous formic acid. Hydrobromide, M.P. 186-187".

2.64 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 3.20 g. of 7-methyl-tetralone-(1) are condensed in an analogous manner (the latter is produced according to Barnett, J. Chem. Soc., 1933, 434). The oily 1-[7'-methyl- 3',4' dihydronaphthyl (1')] 4 phenyl 4 carboethoxy-piperidine (2.93 g.) so obtained and 0.45 g. of anhydrous formic acid are kept for 2 hours at 140. The 1 [7' methyl 1',2',3,4' tetrahydronaphthyl (1')]- 4-phenyl-4-carboethoxy-piperidine so formed is distilled at 10- mm. pressure, B.P. 200210; M.P. 104105, hydrobromide, M.P. 145.

The following compounds are produced in an analogous manner: from 7-isopropyl-tetralone-(1) (produced according to Barnett, J. Chem. Soc., 1933, 434), 1-[7'- isopropyl 1,2',3',4' tetrahydronaphthyl (1')] 4- phenyl-4 carboethoxy-piperidine, M.P. 118-119", hydrobromide, M.P. 149, nitrate, M.P. 179180 (with decomposition): from 4,7-dimethyl-tetralone-(1) (produced according to Phillips, J. Am. Chem. Soc., 77, 3658 (1955)), 1 [4,7 dimethyl 1',2,3',4 tetrahydronaphthyl (1')] 4 phenyl 4 carboethoxy piperidine, nitrate, M.P. 175180 (with decomposition); from 5,6- dimethyl-tetralone(1) (produced according to Barnett, J. Chem. Soc., 1933, 434), 1-[5',6'-dimethyl-1,2,3,4-tetrahydronaphthyl (1')] 4 phenyl 4 carboethoxy-piperidine, M.P. 122, nitrate, M.P. 180; and from 6-chlorotetralone-( 1) (produced according to Schroeder, Ber., 63, 1308 (1930) and 71, 1040 (1938)), 1-[6-chloro-1,2,3, 4-tetrahydrona-phthyl-(1')]-4-phenyl 4 carboethoxypiperidine, nitrate, M.P. 185.

EXAMPLE 2O 47 g. of 1-[3,4'-dihydronaphthyl-(2')]-4-phenyl-4- car-boethoxy-piperidine (see Example 16), 74 g. of methyl iodide and 130 ml. of anhydrous dioxan are refluxed for 14 hours under an atmosphere of nitrogen. The solvent is distilled off in vacuo, the ammonium salt which remains is taken up in abs. ether and filtered off while excluding air, 54 g. of this ammonium salt are dissolved in 350 ml. of diethylene glycol dimethyl ether and 27.8 g. of sodium borhydride, dissolved in 190 ml. of diethylene glycol di methyl ether, are added dropwise to the solution. The reaction mixture is then stirred first for 3 hours at 45 and then for 14 hours at room temperature. The turbid solution is then carefully acidified with dilute sulphuric acid and extracted with ether. The acid solution is made alkaline at with concentrated sodium hydroxide solution and exhaustively extracted with ether. After drying the ether and evaporating, 1-[1'-methyl-1,2,3',4-tetrahydronaphthyl-(2')]-4-phenyl-4-carboethoxy-piperidine is obtained which, after recrystallising twice from methanol, melts at 9799. Sulphate, M.P. 190195.

1 [1' methyl indanyl (2')] 4 phenyl 4 carboethoxy-piperidine (M.P. 98l00) is obtained from l-[indenyl-(2')] 4-phenyl-4-carboethoxy-piperidine in an analogous manner; hydrobromide, M.P. 234235.

EXAMPLE 21 (a) 3.29 g. of 4-(4'-chlorophenyl)-4-carboethoxy-piperidine carbonate (hydrochloride, M.P. 211) (produced analogous to O. Eisleb, Ber., 74, 1443 (1941) from 4-chlorobenzyl cyanide and N,N-bis-(2-chloroethyl)-ptoluene sulphenamide) are dissolved in 50 ml. of toluene and the solution is boiled in a flask fitted with water separator until carbon dioxide is no longer developed and any slight amount of water still contained in the solution is removed. 1.46 g. of tetralone-(2) are then added and the reaction mixture is further heated in a flask fitted with water separator under an atmosphere of nitrogen. The solution is then evaporated in vacuo and the residue, 1-[3,4-dihydronaphthyl-(2)] 4 (4-chlorophenyl)-4 carboethoxy-piperidine melts at 145 when recrystallized from benzene/methanol. 1-[1'-methyl-3,4'-dihydronaphthyl(2)]4-(4"-chlorophenyl)-4-carboethoxy piperidine is obtained in an analogous manner starting from 3.29 g. of 4-(4'-chlorophenyl)-4-carboethoxy-piperidine carbonate and 1.60 g. of 1-methyl-tetralone-(2) (produced analogous to G. Stork, J. Am. Chem. Soc., 76, 2029 (1954)), M.P. 117.

(b) l-[l,2,3,4'-tetrahydronaphthyl-(2)]-4-(4"-chlorophenyl) 4 carboethoxy-piperidine is obtained analogously to Example 8 starting from 3.95 g. of 1-[3,4'- dihydronaphthyl-(2')] 4 (4-chlorophenyl)-4-carboethoxy-piperidine and 0.52 g. of anhydrous formic acid. Hydrochloride, M.P. 222. -1-[1'-methyl-1,2,3',4'-tetrahydronaphthyl- 2) ]-4- 4"-chlorophenyl) -4-carboethoxypiperidine can be produced in an analogous manner from 1-[1-methyl-3',4'-dihydronaphthyl-(2')] 4 (4"-chlorophenyl')-4-carboethoxy piperidine. Hydrochloride, M.P. 208.

EXAMPLE 22 2.46 g. of 4-(2-tolyl)-4-carboethoxy-piperidine (M.P. 168) (produced analogously to O. Eisleb, Ber., 74, 1443 (1941) from o-tolyl'acetonitrile and N,N-bis-(2-chloroethyl)-p-toluene sulphonamide) are dissolved in 50 ml. of toluene and, with 1.46 g. of tetralone-(2) boiled for 12 hours in a flask fitted with water separator. The solution is then evaporated in vacuo and the residue, 1-[3,4'-di-hydronaphthyl (2') ]-4-(o-tolyl)-4-carboethoxy-piperidine, is reduced analogously to Example 18 with 0.51 g. of anhydrous formic acid. The .1-[1',2',3',4'-tetrahyronaphthyl-(2')] 4 (o-tolyl)-4-carboethoxy-piperidine so obtained produces a hydrochloride which melts at 305 (with decomposition).

EXAMPLE 23 1-[1,2,3',4-tetrahydronaphthyl-(2) ]-4-(3" methoxyphenyl) 4 carboethoxy-piperidine, hydrochloride, M.P. 191, is obtained analogously to Example 22 by condensing 2.63 g. of 4-(3'-methoxyphenyl)-4-carboethoxypiperidine (hydrochloride, M.P. 160) (produced analogously to O. Eisleb, Ber., 74, 1443 (1941) from 3-metetrahydronaphthyl-(2) ]-4-phenyl-4-carboethoxy piiperene sulphonamide) with 1.46 g. of tetralone-(Z) and then reducing with formic acid.

EXAMPLE 24 607 mg. of 1-[1' oxo 1,2',3',4 tetrahydronaphthyl- (2') ]-4-phenyl 4 carboethoxy-piperidine (see Example 10) are dissolved in 10 ml. of diethylene glycol dimethyl ether and a solution of 400 mg. of sodium borhydride in 10 ml. of diethyl glycol dimethyl ether is slowly added. The reaction mixture is stirred for 3 hours at 35 and 14 hours at room temperature and the product is then worked up as described in Example 20. 1-[1-hydroxy-1',2,3,4- tetrahydronaphthyl- (2 ]-4-phenyl-4-carbetlroxy piperidine is obtained. After recrystallisation from methylene chloride/pentane, M.P. 153-154". Methane sulphonate, M.P. 151 152.

EXAMPLE 25 760 mg. of 1 [2-hydroxy-1',2',3,4'-tetrahydr0naphthyl-(l)]-4-phenyl 4 carboethoxy-piperidine (see Example 1) are dissolved in a mixture of ml. of ether and 30 ml. of methylene chloride, 282 mg. of bortrifluoride/etherate complex and a solution of 1 g. of diazomethane in 45 ml. of ether are added at 0 and the whole is left to stand for half an hour. The reaction mixture is diluted with 200 ml. of ether and washed with 10% sodium carbonate solution and water. After drying and evaporating the other solution, an oily residue is obtained which is dissolved in hexane and filtered according to Brockmann through 10 times the amount of aluminium oxide activity II. After distilling off the solvent, 1-[2-methoxy 1',2,3',4 tetrahydronaphthyl-(l)]-4-phenyl-4- carboethoxy piperidine remains. After recrystallisation twice from pentane it melts at 54-55 1 7 EXAMPLE 26 200 m1. of 1-[6'-amino-1,2',3,4'-tetrahydronaphthyl- (1) ]-4-phenyl-4-carboethoxy-piperidine (see Example 33) are dissolved in 5 ml. of acetanhydride and the solution is heated for 1 hour at 100. The mixture is evaporated to dryness in vacuo, the residue is dissolved in ether and the solution is washed with diluted sodium hydroxide solution and water. After drying and evaporating, 1-[ 6'- acetylamino-l,2,3',4'-tetrahydronaphthyl (1')]-4-phenyl-4-carboethoxy-piperidine is obtained. On recrystallising twice from ether/pentane, it melts at 123-124".

EXAMPLE 27 200 mg. of 1-[6-acetylamino-l',2,3',4'-tetrahydronaphthy1-(.1')]-4-phenyl 4 carboethoxy-piperidine (see Example 26) are dissolved in 20 ml. of 6 N hydrochloric acid. The solution is heated for 2 hours at 100, the mixture is made alkaline at 0 with dilute sodium hydroxide solution and extracted exhaustively with ether. After drying and evaporating the ether solution, 1-[6'-amino-1,2', 3',4-tetrahydronaphthyl-( 1) ]-4-phenyl-4-carboethoxy-piperidine is obtained. On recrystallisation from ether it melts at 12812-9; dihydrochloride, M.P. 196203.

EXAMPLE 28 500 mg. of a suspension of 50% sodium hydride in parafiin oil is dissolved in 50 ml. of abs. benzene and a solution of 38 g. of 1-[3'-hydroxy-1',2,3,4-tetrahydronaphthyl-(Z)]-4-phenyl-4 carboethoxy-piperidine (see Example 13) in 50 ml. of abs. benzene is added. 1.15 g. of methane sulphonyl chloride dissolved in 50 ml. of abs. benzene is then added dropwise and the reaction mixture is stirred for 14 hours at room temperature. The solvent is then distilled oil? in vacuo, 100 ml. of ether are added to the residue and the insoluble precipitate .is filtered off. On distilling off the solvent from the ethereal filtrate, l- [3' chloro 1',2,3',4' tetrahydronaphthyl (2')] 4- phenyl-4-carboethoxy-piperidine is obtained. On recrystallising twice from chloroform/ ether, it melts at 125126.

EXAMPLE 29 1.15 g. of 1-[3-chloro-l,2',3',4-tetrahydronaphthyl- (2)]-4-phenyl-4-carboethoxy-piperidine are dissolved in 100 ml. methanol, 15 ml. of a methanolic sodium methylate solution (from 900 mg. of sodium and 100 m1. of methanol) are added dropwise and the reaction mixture is refluxed for 1 hour. 200 ml. of ice water are added to the solution and the whole is extracted several times with ether. The other extracts are washed neutral with water and dried. On distilling off the solvent, 1-[1',2-dihydronaphthyl-(2)1-4-phenyl-4-carboethoxy-piperidine is obtained. M.P. on recrystallisation from hexane 123124. Methane sulphonate, M.P. l62163.

EXAMPLE 30 361 mg. of 1-[1,2-dihydronaphthyl-(2')]-4-phenyl-4- carboethoxy-piperidine are dissolved in 200 ml. of ethanol and the solution is shaken at room temperature, in the presence of 50 mg. of platinum catalyst, under an atmosphere of hydrogen (according to Adams). The reaction ceases after 1 mol of hydrogen gas has been taken up. The catalyst is then filtered 01f and 1-[1,2',3',4'-tetrahydronaphthyl-(Z) ]-4-phenyl-4 carboethoxy-piperidine is obtained from the filtrate by distilling off the solvent. Recrystallised from hexane, it melts at 9798; hydrochloride, M.P. 199-200"; methane sulphonate, M.P. l94196 (see Examples 9 and 17).

EXAMPLE 31 (a) 379 mg. of1-[2'-hydroxy-1',2,3',4-tetrahydronaphthyl-( 1') ]-4-phenyl-4-carboethoxy-piperidine are dissolved in 40 ml. of glacial acetic acid, a solution of 1 g. of chromium trioxide in 20 ml. of glacial acetic acid is added and the reaction mixture is left to stand for 14 hours at room temperature. After the excess chromium trioxide has been reduced with 5 ml. of methanol, the acetic acid is distilled off in vacuo, 20 ml. of water are added to the residue and this is made alkaline with concentrated sodium hydroxide solution and exhaustively extracted with ether. The ether extract is washed neutral with water, dried and concentrated, whereupon 1-[2-oxo- 1',2,3,4' tetrahydronaphthyl-( 1) ]-4-carboethoxy-piperidine is obtained as an oil.

(b) 379 mg. of 1-[2'-hydroxy-1',2',3',4-tetrahydronaphthyl-(1)]-4 phenyl 4-carboethoxy-piperidine are dissolved in 5 ml. of abs. pyridine, the chromium trioxide/pyridine complex (from 300 mg. of chromium trioxide and 3 ml. of pyridine) is added and the reaction mixture is left to stand for 14 hours at room temperature. It is then poured in water, exhaustively extracted with ether and the ether extract is washed neutral with water. The l-[2-oxo-l,2', 3, 4-tetrahydronaphthyl-(1)]-4- phenyl-4-carboethoxy-piperidine is obtained in this way as an oil.

EXAMPLE 32 2.64 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 1.34 g. of 1-acetoxy-2-bromotetralin (produced according to Braun and Kirschbaum, Ber., 54, 597 (1921)) are heated for 14 hours at The reaction mixture is then dissolved in ether and 1 N hydrochloric acid and extracted several times with 20 ml. of 1 N hydrochloric acid. The combined acid solutions are then made alkaline with ice cold 1 N sodium hydroxide solution and extracted with ether. Non-reacted 4-phenyl-4- carboethoxy-piperidine is precipitated from the ether extract as carbonate and is filtered off. On distilling off the solvent from the ethereal filtrate, the 1-[2'-hydroxy-1,2', 3,4'-tetrahydronaphthyl-(1)]-4 phenyl-4-carboethoxypiperidine which has been formed by rearrangement and splitting off the acetyl radical, is obtained as an oil. Hydrobromide, M.P. l12-115 (see Example 1).

EXAMPLE 33 2.64 g. of 4-phenyl-4-carboethoxy-piperidine carbonate and 3.78 g. of 6-acetylamino-tetralone-(1), (produced according to Allinger, J. Org. Chem., 27, 70, (1962)), are dissolved in 5 ml. of toluene and the solution is heated in a vessel fitted with a water separator for 4 hours under an atmosphere of nitrogen in an oil bath of 160. After cooling, 0.5 g. of anhydrous formic acid are added to the oily crude product and the whole is kept for 2 hours in an oil bath of The reaction mixture is taken up in ether and extracted with 2 N hydrochloric acid. The acid solution is made alkaline at 0 with concentrated sodium hydroxide solution and extracted with ether. The ether solution is dried, any 4-phenyl-4-carboethoxy-piperidine still present is precipitated, by the addition of Dry Ice, in the form of the carbonate and is filtered off. The filtrate is evaporated and the 1-[6-amino-l',2',3,4'-tetrahydronaphthyl(1')]-4-phenyl-4 carboethoxy-piperidine which remains as an oil is converted into the dihydrochloride by treatment with hydrogen chloride solution.

M.P. 196-203. The acetyl group in the starting material is split off during the reaction.

EXAMPLE 34 5.28 g. 4-phenyl-4-carboethoxy-piperidine carbonate are refluxed with 50 ml. of absolute benzene until a solution of the base is obtained, freeing carbon dioxide. After cooling, a solution of 2.56 g. 1-bromo-7-nitrotetralin (preparation see below) in 20 ml. of absolute benzene is added and left standing overnight. The filtered solution from the precipitated 4-phenyl-4-carboethoxy-piperidine hydrobromide is extracted three times, using 50 ml. of 2 N hydrochloric acid each time. The combined extracts are then made alkaline with concentrated sodium hydroxide solution and extracted several times with 100 ml. of ether each time. The basic starting material which Nitrate 180-185 Hydrobromide 137-140 Tartrate 180-181 Phosphate 177-180 Methanesulphonate 210-215 Sulphate 160-163 1-bromo-7-nitrotetralin is prepared as follows: 800 ml. of sodium borhydride in 20 ml. of methanol are added to a solution of 4 g. of 7-nitrotetralone-1 (prepared according to V. Braun, Liebigs Ann. Chem., 45 1, 40 (1927)) in 100 ml. of methanol. The combined solutions are left standing overnight. After adding 1 liter of Water the solution is slightly acidized (pH 4-5) with hydrochloric acid and then exhaustively extracted with ether. The ether solution is washed neutral, dried with sodium sulphate and evaporated. Melting point of 7-nitrotetralol-1 106- 107. 2 g. of 7-nitrotetralol-1 are dissolved in 50 ml. of absolute ether and cooled to -10. While stirring, a solution of 1 ml. of phosphorus tribromide in 10 ml. of absolute ether is slowly added dropwise so that the temperature does not rise above Then the mixture is slowly warmed to room temperature stirring for another two hours. The solution is poured on ice and the ether phase is washed neutral, dried with sodium sulphate and evaporated. M.P. of 1-bromo-7-nitrotetralin, 70.

EXAMPLE 35 g. 1-[7'-nitro-1,2',3',4'-tetrahydro-naphthyl-(1')]-4- phenyl-4-carboethoxy-piperidine are dissolved in 50 ml. of ethanol and the solution is warmed in a water bath. To this solution are added 2 ml. of hydrazine hydrate and about 500 ml. Raney nickel in an ethanol suspension. After the solution has become colorless (about minutes) the catalyst is filtered off. The solution is poured into ten times the amount of water and exhaustively extracted with ether. The ether phases are washed neutral, dried with sodium sulphate and evaporated.

The resulting 1-[7=amino-1,2',3',4'-tetrahydro-(1')]- 4-phenyl-4-carboethoxy-piperidine crystallizes from ether/ petroleum ether. M.P. l07-109.

M.P. dinitrate (dec.) 210-2l5 (from methanol/ ether).

EXAMPLE 36 1 [6-fiuoro 1',2,3',4' tetrahydronaphthyl-(1')]-4- phenyl-4-carboethoxy-piperidine is prepared analogously to Example 34 starting with 5.28 g. 4-phenyl-4-carboethoxy-piperidine carbonate and 2.29 g. 1-bromo-6-fluorotetralin.

Nitrate, M.P. 180-18-1 and Sulphate, M.P. 195-200 from methanol/ether.

The 1-bromo-6-fiuorotetralin which is used is prepared analogously to the 1-bromo-7-nitrotetralin described in Example 34, starting with 6-fluorotetralone-1 (according to Allinger, J. Org. Chem, 27, 70 (1962)).

EXAMPLE 37 l [6'-fluoro 1,2',3',4' tetrahydro-naphthyl-(1')]- 4-(4'-chloro-phenyl)-4-carboethoxy-piperidine is prepared analogously to Example 21 starting with 5.98 4-(4'-chlorophenyl)-4-carboethoxy-piperidine carbonate and 2.29 g. 1-bromo-6-fluorotetralin,

20 Nitrate, M.P. loo-163 and Sulphate, M.P. 2'l0-2l2 from methanol/ ether.

EXAMPLE 38 2 g. 1-[7'-amino-1,2,3,4'-tetrahydro naphthyl]-4- phenyl-4-carboethoxy-piperidine are dissolved in 30 ml. of formic acid. 2 ml. of 30% formaldehyde solution are added and the solution is refluxed two hours. Then 2 ml. of concentrated hydrochloric acid are added and most of the formic acid is evaporated off in vacuo. The mixture is dissolved in 100 ml. water, made alkaline with concentrated sodium hydroxide solution and extracted three times, using 100 ml. ether each time. The combined ether phases are washed neutral, dried with sodium sulphate and evaporated. The residue is dissolved and recrystallized from ether/petroleum ether. The 1-[7'-dimethylamino-1',2,3,4-tetrahydro-naphthyl] 4 phenyl- 4-carboethoxy-piperidine so obtained melts at -105.

We claim:

1. A compound of the formula R is lower alkyl,

R is phenyl, lower alkylphenyl, lower alkoxyphenyl,

chlorophenyl or bromophenyl,

R is hydrogen, chloro, lower alkyl or lower alkoxy,

and each of R and RC. is hydrogen or lower alkyl.

2. A compound of the formula wherein R is lower alkyl,

R is phenyl, lower alkylphenyl, lower alkoxyphenyl,

chlorophenyl or bromophenyl,

and R is hydrogen or lower alkyl.

3. A 1-[3,4'-dihydronaphthyl-(2)]-piperidine according to claim 1 wherein R is ethyl, R is phenyl and R R and R' are hydrogen.

4. A l-[3',4-dihydronaphthyl-(2')]piperidine according to claim 1 wherein R is ethyl, R is phenyl, R and R are hydrogen and R; is 1-methyl.

5. A 1-[3,4'-dihydronaphthyl-(2')]-piperidine according to claim 1 wherein R is ethyl, R is 4"chlorophenyl, R R and R'., are hydrogen.

6. A 1-[3',4'-dihydronaphthyl-(2)]-piperidine according to claim 1 wherein R is ethyl, R is 4"-chlorophenyl, o-tolyl or 3"-methoxyphenyl, R and R are hydrogen and Kris 1-methyl.

7. A l-[indenyl-(Z')]piperidine according to claim 2 wherein R is ethyl, R is phenyl and R is hydrogen.

References Cited FOREIGN PATENTS 269,708 10/ 1964 Australia.

HENRY R. JILES, Primary Examiner G. THOMAS TODD, Assistant Examiner US. CL X-Ri 260-2, 294, 999 

